Unveiling the IL-36/IFNK axis in sex-biased generalized pustular psoriasis

Summary: Abstract Body: Generalized pustular psoriasis is a severe subtype of psoriasis characterized by significant morbidity, mortality, and a pronounced female sex bias. This condition is associated with elevated expression of IL-36 cytokines, including IL-36A, IL-36B, and IL-36G, as well as the IL-36 receptor antagonist (IL-36RA/IL36RN). Single-cell and spatial transcriptomic analyses revealed that IL-36 activity is primarily localized to the supraspinous layer of the epidermis and acts downstream of IL-17A and TNF pathways. Using CRISPR/Cas9-mediated knockout, we demonstrated that deleting IL36G and its receptor IL36R in keratinocytes significantly suppressed IL-17A and TNF responses (p<0.001), suggesting a prominent role for IL-36G in epidermal inflammation. Further, RNA sequencing of primary keratinocytes (n=47) revealed a marked sex-specific response, with female keratinocytes exhibiting a more robust pro-inflammatory reaction compared to male keratinocytes (p<0.001). Female keratinocytes also showed elevated expression of type I interferon, IFNK (p<0.001; FC-3.84), and its signature genes, such as MX1 (p<0.001; FC-4.78), indicating a potential interaction between IFN-κ and the IL-36 axis. Moreover, RNA sequencing data from 3D skin rafts showed decreased expression of both TNFRSF25 (TNFSF15 receptor) and IFNK during epidermal differentiation, suggesting coordinated regulation. Spatial sequencing analysis identified the close proximity of TNFSF15+ neutrophils to IL36G+ TNFRSF25+ keratinocytes in the epidermis of pustular psoriasis lesions. These findings provide novel insights into IL-36 biology, highlighting its role in IL-17 and TNF responses within the epidermis. The sex-specific IL-36 response and its interaction with the TNFSF15 and IFNK axes may contribute to the predominance of pustular psoriasis in women, offering potential therapeutic targets for managing this condition, particularly in female patients. Mrinal K. Sarkar¹, Anthony M. Coon¹, Christopher Cole¹, Rundong Jiang¹, Craig Dobry¹, Lam C. Tsoi¹, Michelle Kahlenberg², Johann E. Gudjonsson¹ 1. Dermatology, University of Michigan, Ann Arbor, MI, United States. 2. Rheumatology, University of Michigan, Ann Arbor, MI, United States. Adaptive and Auto-Immunity